Biology subjects

Ip, P. P. C.

Publications and source records attributed to Ip, P. P. C..

4 recordsLinked to original sources

bioRxiv2025

Cancer-specific sialylation of insulin-like growth factor 1 receptor impairs therapeutic antibody binding and efficacy

Despite extensive efforts to develop insulin-like growth factor (IGF1R)-targeted therapies for various malignancies, none has received clinical approval in the past two decades. Here, we reveal that N-glycan sialylation significantly decreases recognition by the humanized monoclonal anti-IGF1R antibody ganitumab across various cancer types, reducing its efficacy both in vitro and in vivo. Sialoforms of IGF1R are virtually absent in normal cells, indicating that the modification is tumor-specific. Pharmacological inhibition of sialyltransferases significantly sensitizes metastatic tumors to ganitumab in a ganitumab-resistant ovarian cancer model. Enzymatic removal of sialic acids from tissue sections resulted in marked enhancement in antibody binding to ovarian cancer patient tumors, but not normal tissues. Upregulation of 2-6 sialyltransferase ST6GAL1 in tumor tissues was found to be responsible for sialylation of IGF1R. Consequently, ST6GAL1-high tumors were more likely to benefit from desialylation-mediated enhancement of ganitumab binding. Furthermore, through comprehensive glycoproteomics analysis, structural prediction, and molecular dynamics simulation, we identify Asn-607 (N607) as a crucial site harboring sialylated glycans. Mechanistically, N607 glycosylation destabilizes the IGF1R-ganitumab complex. Overexpression of IGF1R Asn-607-Gln (N607Q) mutant in IGF1R-knockout cancer cells increases ganitumab efficacy compared to wild-type IGF1R in vivo. Taken together, these findings highlight sialylation as a common barrier in IGF1R-targeted therapies and provide crucial insights for therapy enhancement in cancer and patient stratification for future clinical trials. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/682592v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@17c6d5corg.highwire.dtl.DTLVardef@1efe2f7org.highwire.dtl.DTLVardef@1dd05aorg.highwire.dtl.DTLVardef@159fb23_HPS_FORMAT_FIGEXP M_FIG C_FIG Synopsis2-6 sialylation of IGF1R Asn-607 by ST6GAL1 is prevalent in cancer. This modification disrupts the interaction of IGF1R with therapeutic mAb ganitumab. Removal of sialylation augments ganitumab efficacy.

cancer biology↗

bioRxiv2024

Dynamin 1-mediated endocytic recycling of glycosylated N-cadherin sustains the plastic mesenchymal state to promote ovarian cancer metastasis

Epithelial-to-mesenchymal transition (EMT) is a key process that confers metastatic plasticity to ovarian cancer cells, enabling them to disseminate aggressively throughout the peritoneal cavity and contributing to poor clinical outcomes for patients. However, a pharmacologically exploitable driver of EMT in ovarian cancer has yet to be identified. To address this, we utilized a master regulators algorithm to prioritize EMT regulators from a dataset of over 8,000 patient samples, including multidimensional omics data from more than 20 cancer types in TCGA. Further analysis identified dynamin-1 (DNM1), an endocytic regulator, as a novel master regulator of EMT in ovarian cancer. Clinically, DNM1 overexpression was found to be associated with the mesenchymal subtype and advanced/metastatic stages of ovarian carcinomas. Molecular assays revealed that DNM1 upregulates N-cadherin, a hallmark mesenchymal marker, by promoting its endocytosis and recycling, thereby inducing cell polarization and motility. In addition, integration of ATAC-seq and RNA-seq analyses uncovered the repression of beta-1,3-galactosyltransferase (B3GALT1), a glycosyltransferase, in metastatic cells. B3GALT1-mediated glycosylation hindered the recycling of N-cadherin. Functional studies demonstrated that depletion of DNM1 or pharmacological inhibition of endocytic recycling significantly impaired cell polarity, migration, and also cancer stemness. Importantly, in vivo experiments showed that the loss of DNM1 significantly suppressed peritoneal metastatic colonization. Interestingly, metastatic cells with elevated DNM1-mediated endocytosis showed increased susceptibility to nanoparticle delivery. Collectively, these results establish the DNM1-N-cadherin axis as an important regulator of EMT-associated ovarian cancer metastasis and suggest its potential as a biomarker for targeted nanodrug therapy.

cancer biology↗

bioRxiv2024

Bola-amphiphilic dendrimer empowers imatinib to target metastatic ovarian cancer stem cells via beta-catenin-HRP2 signaling axis

Ovarian cancer is the leading cause of death among all gynecological malignancies, and drug resistance renders the current chemotherapy agents ineffective for patients with advanced metastatic tumors. We report an effective treatment strategy for targeting metastatic ovarian cancer involving a nanoformulation (Bola/IM) - bola-amphiphilic dendrimer (Bola)-encapsulated imatinib (IM) - to target the critical mediator of ovarian cancer stem cells (CSCs) CD117 (c-Kit). Bola/IM offered significantly more effective targeting of CSCs compared to IM alone, through a novel and tumor-specific {beta}-catenin/HRP2 axis, allowing potent inhibition of cancer cell survival, stemness and metastasis in metastatic and drug-resistant ovarian cancer cells. Promising results were also obtained in clinically relevant patient-derived ascites and organoids, alongside high tumor-oriented accumulation and favorable pharmacokinetic properties in mouse models. Furthermore, Bola/IM displayed synergistic anticancer activity when combined with the first-line chemotherapeutic drug cisplatin in patient-derived xenograft mouse models, without any adverse effects. Our findings support the use of Bola/IM as a nanoformulation to empower IM, providing targeted and potent treatment of metastatic ovarian cancer. Our study thus represents a significant advancement towards addressing the unmet medical need for improved therapies targeting this challenging disease.

cancer biology↗

bioRxiv2024

P-cadherin mechanoactivates tumor- mesothelium metabolic coupling to promote ovarian cancer metastasis

Peritoneal metastasis exacerbates the prognosis of ovarian cancer patients. Adhesion of cancer cells to mesothelium is a rate-limiting prerequisite for this process. How metastatic cells sense and respond to the dynamic biomechanical microenvironment at the mesothelial niche to initiate metastatic lesions remains unclear. Here, the study demonstrates that highly metastatic (HM), but not non-metastatic (NM) ovarian cancer cells, selectively activate the peritoneal mesothelium. Atomic force microscopy reveals that HM cells exert increased adhesive force on mesothelial cells via P-cadherin, a cell-cell adhesion molecule abundant in late-stage tumors. Transcriptomic and molecular analyses show that mechanical induction of P-cadherin enhances lipogenic gene expression and lipid content in HM cells by SREBP1. P-cadherin activation does not affect lipogenic activity but induces glycolysis in the interacting mesothelium. Targeted lipidomic analysis reveals that lactate produced by the glycolytic mesothelium facilitates metastatic outgrowth as a direct substrate for de novo lipogenesis. Inhibiting lactate shuttling via nanodelivery of siRNA targeting P-cadherin or MCT1/4 transporters significantly suppresses metastasis in mice. The association of high fatty acid synthase in patient metastatic samples and increased P-cadherin expression supports enhanced de novo lipogenesis in the metastatic niche. The study reveals P-cadherin-mediated mechano-metabolic coupling as a promising target to restrain peritoneal metastasis.

cancer biology↗